Differentially Activated Macrophages Orchestrate Myogenic Precursor Cell Fate During Human Skeletal Muscle Regeneration

TLDR

Macrophages can be either beneficial or harmful to tissue repair depending on their activation state, and they are essential for skeletal muscle repair by influencing myogenic precursor cells, though these interactions remain incompletely understood. The study investigates how differentially activated macrophages interact with myogenic precursor cells during adult human skeletal muscle regeneration. The authors performed in vitro co‑culture experiments and in vivo time‑course analyses of macrophage and myogenic markers in regenerating human muscle. In vitro, pro‑inflammatory macrophages inhibited MPC fusion while anti‑inflammatory macrophages promoted differentiation and myotube formation, and in vivo human muscle regeneration showed proliferating MPCs linked to pro‑inflammatory macrophages and differentiating MPCs linked to anti‑inflammatory macrophages, demonstrating that macrophages sequentially orchestrate myogenesis through inflammatory activation.

Abstract

Macrophages (MPs) exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for adult skeletal muscle repair, notably by acting on myogenic precursor cells. However, these interactions have not been fully characterized. Here, we explored both in vitro and in vivo, in human, the interactions of differentially activated MPs with myogenic precursor cells (MPCs) during adult myogenesis and skeletal muscle regeneration. We showed in vitro that through the differential secretion of cytokines and growth factors, proinflammatory MPs inhibited MPC fusion while anti-inflammatory MPs strongly promoted MPC differentiation by increasing their commitment into differentiated myocytes and the formation of mature myotubes. Furthermore, the in vivo time course of expression of myogenic and MP markers was studied in regenerating human healthy muscle after damage. We observed that regenerating areas containing proliferating MPCs were preferentially associated with MPs expressing proinflammatory markers. In the same muscle, regenerating areas containing differentiating myogenin-positive MPCs were preferentially coupled to MPs harboring anti-inflammatory markers. These data demonstrate for the first time in human that MPs sequentially orchestrate adult myogenesis during regeneration of damaged skeletal muscle. These results support the emerging concept that inflammation, through MP activation, controls stem cell fate and coordinates tissue repair.